Impact of Guideline-Directed Statin Prescriptions on Cardiovascular Outcomes by Race in a Real-World Primary Prevention Cohort

Background Data on real-world statin prescription in large, private health care networks and impacts on primary prevention of atherosclerotic cardiovascular disease (ASCVD) outcomes across race are scarce. Objectives The purpose of this study was to investigate the impact of statin prescription on ASCVD outcomes within and across race in a large, nongovernmental health care system. Methods Statin prescription in Black and White patients without ASCVD was evaluated (2013-2019). Guideline-directed statin intensity was defined as at least “moderate” for intermediate and high-risk patients. Statin prescription at index and ASCVD outcomes at follow-up (myocardial infarction/revascularization, stroke, mortality) were assessed via electronic health care records using International Classification of Diseases-9 and 10 codes. Cox regression models, adjusted for CVD risk factors, were used to calculate HRs for association between statin prescription and incident ASCVD events across race. Results Among 270,079 patients, 7.6% (n = 20,477) and 92.4% (n = 249,602) identified as Black and White, respectively. Significantly fewer Black patients were prescribed statin therapy than White patients (13.6% vs 19.0%; P < 0.001). At a mean follow-up of 6 years, patients with “no statin” prescription vs guideline-directed statin intensity showed increased ASCVD in Black patients (HR: 1.40 [95% CI: 1.05-1.86]), and White patients (HR: 1.32 [95% CI: 1.21-1.45]; P < 0.05) and all-cause mortality. Intermediate and high-risk Black patients faced a 17% higher risk of mortality compared to White patients. However, the interaction between race and statin prescription was not a significant predictor of incident ASCVD events. Conclusions Statins remain underprescribed. Although Black patients received proportionally less statin prescription than White patients, this was not associated with higher risk of mortality in Black patients.

3][4] Additionally, Black patients are often disproportionately burdened by more frequent and severe ASCVD. 4Thus, the opportunity to promote equity in health outcomes in the United States persists.
Assessing patient risk of ASCVD and eligibility for statin therapy is key for primary prevention in vulnerable populations.In the United States, the American College of Cardiology/American Heart Association (ACC/ AHA) guidelines are preferred for screening and identification of patients who are at risk for ASCVD events. 5The 2013 ACC/AHA guidelines specifically were the first to recommend calculating patient 10-year risk for ASCVD using the ASCVD Risk Estimator. 6These validated tools for risk estimation are useful for rapid decision-making in the prevention and management of cardiovascular disease.Despite these efforts, statin prescription in the real-world lags behind guideline recommendations and remains suboptimal. 710] Broadly, individual racism, social determinants of health, and institutional racism are all known to influence cardiovascular disease outcomes related to racial discrimination. 8The disparity in mortality between Black and White patients has even been reiterated in smaller analyses that adjust for markers of socioeconomic status (SES) such as neighborhood SES, income, education, and health insurance. 9This troublingly emphasizes the need to address structural and systemic drivers of these disparities.Given the role of statin therapy in ASCVD prevention, continued assessment of how statin prescription in Black and White patients translates to real-world outcomes could provide useful insight into where highest yield efforts can be made.
Evidence has shown that failure to adhere to guideline recommendations in eligible populations carries real-world hazard. 7Compared to patients who are prescribed the guideline-directed statin intensity (GDSI), patients with no statin prescription have a greater risk of ASCVD and mortality. 7Our study aims to assess the real-world prescription of GDSI in Black and White patients within a large health care network and evaluate if the current prescription of statins can be implicated in differences of ASCVD outcomes within and across race.

METHODS
The design and rationale of our initial investigation into statin prescription has previously been described in extensive detail. 7 were included (Supplemental Figure 1).As this study focused on primary prevention of ASCVD, patients were excluded if they had a baseline history of car- Hay et al Statin Prescription and Outcomes Across Race The appropriate GDSI for a given patient was Hay et al Data are presented as N, %, or adjusted HRs (aHRs) for mortality in high-risk patients.Outcome aHRs were compared within race between patients with no statin and guideline-directed statin intensity (GDSI), and directly across race between White and Black patients.High-risk patients were defined per the 10-year ASCVD risk categories with a risk $20%.High-risk GDSI was moderate or high intensity.Statin intensity and HR adjustments for cardiovascular risk factors are as defined in Methods.*P for trend <0.05.ASCVD ¼ atherosclerotic cardiovascular disease.
Hay et al respectively.The interaction between statin prescription and race was not a significant predictor for any of the outcomes assessed for those at intermediate and high risk (Supplemental Table 2).

DISCUSSION
In this retrospective analysis of statin prescription within a large, nongovernmental, real-world cohort of patients in the greater Western Pennsylvania area, we sought to categorize how statins are currently prescribed, the subsequent effect on risk of ASCVD, and if the prescription of these medications can be associated with health disparities in ASCVD outcomes across race.We found that statin prescription continues to be associated with decreased risk of ASCVD events and all-cause mortality.Black and White patients at high risk that were not prescribed any statin on index were at approximately 56% higher risk of mortality compared to similar race patients that were prescribed GDSI.There also continues to be significant underprescription of statin therapy in the community at large, as less than half of all patients at high  Statin Prescription and Outcomes Across Race risk were prescribed a statin on index.Overall, Black patients were prescribed proportionally less statin therapy than White patients and this effect was most profound in patients at borderline and intermediate risk.We also found continued overall disparities in outcomes between Black and White patients: Black patients classified as intermediate and high risk had a 17% increase in risk of all-cause mortality compared to similarly stratified White patients.Risk for incident myocardial infarction and stroke was similar when compared across race for these groups.However, the interaction term between race and statin prescription was not a significant predictor of the outcomes assessed.Thus our findings suggest that the beneficial effects of statin prescription on mortality were similar in both races.
The data support the known protective association between statin therapy and reduced risk of ASCVD events. 1,5,7This is most obvious in patients whose 10year ASCVD risk profiles are "high."At the median follow-up of 6 years in this cohort, both Black and White patient sample showed that patients who were designated with "no statin" prescribed at their index date were at an increased risk of defined ASCVD outcomes when compared to patients within race who were prescribed with the GDSI.This is in line with the robust literature advocating the efficacious, low-risk profile of statins. 12e real-world implementation of guidelines for statin prescription in primary prevention of ASCVD remains a crucial area for improvement.In our data, less than half of patients at high risk had no evidence Data are presented as HRs and CIs of CAD (MI and revascularization), stroke (ischemic), ASCVD outcomes (CAD and ischemic stroke), and mortality across 10-year risk categories.The 10-year ASCVD risk categories were defined as "low risk" (<5%), "borderline" (5%-7.4%),"intermediate" (7.5%-19.9%),and "high" risk ($20%).GDSI for each risk category is defined per ACC/AHA cholesterol guidelines of 2013 and 2018, and models of association were adjusted for the pooled cohort equation variables; both described in Methods.a P for trend <0.05.b P for trend <0.001.
CAD ¼ coronary artery disease; other abbreviation as in Table 1.
Hay et al Statin Prescription and Outcomes Across Race of a statin prescription on index.While concerning, there is optimism for improvement as patients not receiving a statin despite eligibility report that a leading reason for doing so was never being counseled by their clinician on starting therapy. 13It is therefore possible that noninitiation of statin therapy accounts for a sizeable portion of the underprescription observed in our model.Fortunately, patients with no history of statin prescription are generally amenable to trialing statin therapy and given that statins are relatively affordable and welltolerated, our results emphasize an opportunity for realistic improvement in the primary prevention of ASCVD. 13Excluding low-risk patients in our study, a plurality of patients were classified as intermediate risk which troublingly yielded some of the highest disparities in statin prescription rates; approximately a 9% difference between Black and White patients.
This intermediate risk designation may pose a unique challenge for providers in reliably assessing patient ASCVD risk, therefore improving provider recognition of patient ASCVD risk and statin eligibility may be a fruitful avenue of action.It will likely become of greater importance to refine risk assessment processes for patients who would benefit from intervention and offering of statin prescription, especially as machine learning, artificial intelligence, and precision medicine continue to gain inertia. 14amining across race, we found worse mortality outcomes and inequitable statin prescriptions for Black patients when compared to White.However, we did not find a significant interaction between statin prescription, mortality, and race in our current analysis.Precise explanations for the findings at hand are beyond the scope of our analysis; however, we suspect the stress and hazard of sustained structural inequities in society to be primarily responsible for the mortality outcomes we observed. 15,16In the context of statin utilization, factors such as age, race, sex, poverty, and health insurance rates have previously been seen to have compounding negative impacts on use prevalence of these medications. 17grettably, such effects are potentially intensified in context of differences across race in perceptions of cardiovascular risk and statin safety. 18Beyond statin utilization, markers of SES have been theorized and observed to have profoundly negative associations with all-cause and cardiovascular mortality. 8,9Per the Pittsburgh Inequities across Gender and Race (PIGR) Report, Pittsburgh as a case-study is known to suffer significantly from racial disparities across these determinants. 16Black and White residents of Pittsburgh differ significantly in poverty rates, income, employment rate and type, and education level with Black residents bearing the unfavorable side of comparison within each. 16The overall mortality rate, and rate of death by cardiovascular disease for Black residents in Pittsburgh was higher than that for Black residents in 98% of similarly sized cities. 16 Although our model does not specifically account for social determinants of health, our results suggest that statin prescription is not currently implicated in the worse mortality outcomes for Black patients.As such, known socioeconomic disparities are likely to be exercising significant influence over the mortality outcomes we observed in our current analysis.
A uniquely worrying discrepancy in the demographic makeup of our study is that approximately 7.5% of our study sample was Black, whereas the general proportion of Black residents in Pittsburgh is documented to be about 22%. 16While our sample is partially derived from facilities outside of the city limits of Pittsburgh, most major facilities are located within city limits.Although our data are sourced from a broad variety of hospitals and clinics in Western Pennsylvania, this discrepancy does limit the overall generalizability of our data as this level of incongruency may be driven by region-specific factors.
However, this amplifies the concern for the health disparities across race that we have categorized as it appears that our data are not fully capturing a sizeable proportion of Black residents for reasons most likely related to access to care.
Unfortunately, our data are likely to be yet another reflection of continued inequities across race in our geographic area.The health care industry is known to have had a significant role in the promulgation of these inequities through many unethical and abusive acts toward communities of color. 19Substantive efforts pursuant of equity in health care are wideranging; with areas of potential impact including but not limited to promotion of diversity, equity, and Abbreviations as in Tables 1 and 2.

CONCLUSIONS
Our data from a large, real-world health care system show that statins remain underused in both Black and White patients.Real-world prescription of statins is associated with lowered risk of adverse ASCVD outcomes.Black patients from our sample were overall observed with an increased risk of mortality compared to White patients.Despite this, statin prescription did not interact significantly with race to impact prediction of the ASCVD outcomes measured.

FUNDING SUPPORT AND AUTHOR DISCLOSURES
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

1 A
diovascular disease, defined by the presence of International Classification of Diseases-9th Revision (ICD-9) and/or -10th Revision (ICD-10) code for any of the following: coronary artery disease (CAD, including myocardial infraction, angina, and revascularization, and congestive heart failure) stroke or cerebrovascular disease, transient ischemic attack, peripheral vascular disease, or rhabdomyolysis. 7Patients identified as receiving hospice care or care within a skilled nursing facility were also excluded.COVARIATES AND POOLED COHORT EQUATION-DERIVED RISK.Baseline characteristics of patients were defined using data within 180 days of their index date, as described above.These included sociodemographic data (age, sex, and race), as well as relevant social and clinical history such as smoking status, body mass index, heart rate, prescription of statin, antihypertensives, or aspirin, low-density lipoprotein cholesterol (LDL-C) level, high-density lipoprotein cholesterol (HDL-C) level, diagnosis of diabetes as well as Elixhauser Comorbidity Index scores. 11Patient race classification was selfidentified.All data were assessed within the 180-day window after the index date.The cohort was divided into one of the following pooled cohort equation-derived 10-year risk categories: low risk (<5%), borderline risk (5%-7.4%),intermediate risk (7.5%-19.9%),and high risk ($20%).GDSI was defined per the ACC/AHA cholesterol guidelines of 2018.

J
A C C : A D V A N C E S , V O L . 3 , N O . 1 : Dr Suresh Mulukutla, Vice President and Chief Data and Analytics Officer, UPMC HSD Associate Professor of Medicine, Epidemiology and Clinical and Translational Science, Department of Medicine at the University of Pittsburgh School of Medicine, 200 Lothrop Street, Forbes Tower 11080, Pittsburgh, Pennsylvania 15213, USA.E-mail: mulukutlasr@upmc.edu.PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Statin therapy remains a useful agent in the real-world reduction of adverse ASCVD outcomes.In the absence of a significant interaction between statin prescription and race in predicting adverse ASCVD events, the data suggest looking beyond pharmaceutical intervention with statins to reduce disparities in cardiovascular disease outcomes.TRANSLATIONAL OUTLOOK: The data in our study illustrate that despite overall increased risk of mortality in Black patients at high risk of ASCVD, statins did not significantly interact with race to impact this outcome.Although statins were observed to be efficacious within race for the mortality outcome, this likely indicates other culprit variables, likely to be social determinants.Further research from large-health systems will benefit from inclusion of social determinants of health in patient demographic data.Additionally, this retrospective cohort study also serves as an example of in-house data analysis within a large, private health care system.As the roots of artificial intelligence in medicine continue to grow, efforts such as ours may serve as a nidus for further research in this area developing geography specific clinical tools.Hay et al J A C C : A D V A N C E S , V O L . 3 , N O . 1

Table 3 ,
Supplemental Table1).This was most pro- 3 1 Statin Prescription and Outcomes Across Race COMPARISON OF EVENT FREQUENCIES BETWEEN BLACK AND WHITE PATIENTS.Stroke was the least common outcome in both races across the borderline, intermediate, and high-risk categories (Table 2).The frequency of each ASCVD outcome increased gradually as the risk level increased.Nominally, the majority of incident ASCVD events and mortality occurred in patients at intermediate and high risk for both races.The proportion of patients with each of the observed outcomes within a given risk category was highest in those at high risk.ADJUSTED HRS FOR BLACK AND WHITE PATIENTS FOR EVENTS ACROSS ASCVD RISK CATEGORIES.At a median follow-up of 6 years, both Black and White patients with no statin prescription at their index date were at higher risk of defined ASCVD outcomes when compared to those with a prescription at GDSI (aHR Mortality-White : 1.57 [95% CI: 1.43-1.71],P < 0.05).For Black patients, those who were at intermediate risk of ASCVD with no statin prescription at their index date were associated with a significantly higher risk for defined ASCVD outcomes (aHR ASCVD : 1.33 [95% CI: 1.05-1.70],P < 0.05) as well as mortality (aHR Mortality : 1.74 [95% CI: 1.34-2.25])compared to similar risk Black CENTRAL ILLUSTRATION Statin Prescription Associated With Reduced Risk of Mortality, but Not Racial Disparity in Outcomes Hay EJ, et al.JACC Adv.2024;3(10):101231.

TABLE 3
Association of Adverse ASCVD Outcomes With Statin Prescription per 10-Year ASCVD Risk Categories Within Race

TABLE 2
Frequency of Outcome by 10-Year ASCVD Risk and Race

TABLE 4
Association of Adverse ASCVD Outcomes Between Race perData are presented as HRs and CIs of CAD (MI and revascularization), stroke (ischemic), ASCVD outcomes (CAD and ischemic stroke), and mortality across 10-year risk categories.The 10-year ASCVD risk categories were defined as "intermediate" (7.5%-19.9%)and "high" risk ($20%).Models of association adjusted for the pooled cohort equation variables and covariates including statin prescription as described in Methods.a P for trend <0.05.b P for trend <0.001.